HIF-1α Overexpression and Experimental Murine Atherosclerosis

Background-Lymphocytes play an important role in the progression of atherosclerosis. Recently, hypoxia inducible factor-1 (HIF-1) was found to attenuate inflammation by regulating T cell activation and cytokine production. We studied the effects of overexpression of HIF-1 alpha in ApoE knockout murine lymphocytes, on experimental atherosclerosis. Methods and Results-ApoE(-/-) mice were submitted to intravenous hydrodynamic injection of empty plasmid or HIF-1 alpha P564A (HIF-1 alpha mutated stabilized construct). Robust expression of HIF-1 alpha was evident in spleen cells of recipient animals. Increased expression of IL-10 as well as decreased expression of IFN-gamma was measured in splenocytes of HIF-1 alpha-treated mice by RT-PCR. One week postinjection, antibody array analysis revealed a pattern consistent with a T helper 1 to T helper 2 shift. On sacrifice, assessment of aortic sinus lesions revealed a significant reduction in plaque size in HIF-1 alpha injected mice. A reduced expression of IFN-gamma was evident in CD4+ spleen-derived lymphocytes and aortas of HIF-1 alpha-injected mice. Conclusions-HIF-1 alpha expression in mouse lymphocytes is associated with a reduced IFN-gamma expression and attenuation of experimental atherosclerosis. (Arterioscler Thromb Vasc Biol. 2009; 29: 665-670.)